Immune system damage may explain ineffectiveness of high-dose radiation against lung cancer

When it comes to using radiation against
lung cancer, preliminary clinical studies were pretty clear: More is better. So
why did a large phase 3 clinical trial find
exactly the opposite – that stage III non-small cell lung cancer patients
treated with higher doses of radiation actually had shorter overall survival than patients treated with lower-dose
radiation?

“At first glance, you might think that
when you give a higher dose of radiation it’s simply too toxic – there are just
too many side effects and the benefit does not outweigh the harm. But in this
trial, if you look at grade 3-5 toxicities, there was no statistically significant
difference between the high- and low-dose radiation arms, and furthermore the
absolute number of treatment-related deaths was quite small as a whole. Even
more interestingly, tumor control was actually worse in the high-dose arm of the study, which is not easily
explained by increased toxicity,” says Sameer K. Nath, MD, University of
Colorado Cancer Center investigator and assistant professor in the CU School of
Medicine Department of Radiation Oncology.

The unexpected findings have vexed researchers since the study closed in 2013. Now a new study by Nath and CU Cancer Center colleagues offers an interesting answer: Blame it on the immune system. That’s because radiation used in the lung doesn’t stay in the lung. This radiation hits blood passing through lung and heart as well. And compromising the immune components of blood removes an important ally in the body’s fight against cancer.

One reason has to do with the way
anti-cancer radiation treatment works. Of course, radiation kills cells –
oncologists try to focus radiation onto tumor tissue so that it primarily kills
cancer cells. But not all cancer
cells die immediately from radiation. Many of these cells are only damaged and
it falls to the immune system to recognize and eliminate these cells with DNA
damage.

“Over the last decade, a lot of research supports
the idea that a functional immune system plays a key role in tumor cell killing
following the DNA damage created by radiation therapy,” Nath says.

But if radiation impairs the immune
system, these tumor cells with DNA damage may be left to survive and ultimately
escape immune-mediated removal.

“Our hypothesis is that higher doses of
radiation to the immune system is contributing to worse survival in those
patients,” Nath says.

To test this hypothesis, Nath and
colleagues used a sophisticated computer model to define the estimated dose of
radiation to immune cells (EDRIC) delivered during treatment. Then they looked
at a new population of patients: Could EDRIC predict survival in 117 patients
with stage III non-small cell lung cancer treated at UCHealth University of
Colorado Hospital between 2004 and 2017?

“We show that the estimated dose of
radiation to immune cells is an important predictor of tumor control and
survival. In fact, it ends up being one of the most important predictors,”
Nath says. “It’s a really thought-provoking finding because radiation effects
on the immune system isn’t something the field has focused on in the past.”

Nath cautions that radiation remains a
backbone treatment for the management of stage III non-small cell lung cancer,
and although radiation dose to the immune system may lessen the benefit of radiation,
several clinical trials have established a clear survival benefit of radiation
in this population.

“What is really exciting is that now that
we have ways to estimate this radiation dose, we can look at sparing the immune
system as an organ-at-risk,” he says. “We think it is a modifiable risk factor.
Now we can focus on methods to minimize dose and in doing so, we will be able
to maximize the benefit of radiation to these patients.”

Though more work is needed to confirm the
current findings and to define best practices for immune-sparing radiation
therapy, Nath suggests that it may be useful to reduce the time over which
radiation is delivered and the number of treatments to restrict the number of
immune cells damaged.

“As you give each fraction of radiation
to the chest, there’s a certain volume of blood that’s in the field. Many of the
lymphocytes in that field will be killed and as you repeat each treatment, you
keep hitting a different volume of blood, and overall end up depleting that circulating
pool. If we reduce number of radiation fractions or give the dose over a shorter
time period, we would be hitting less blood, overall,” Nath says.

Additional immune-sparing strategies for
future study may include the use of more focused forms of radiation that allow
doctors to spare areas that contain more circulating immune cells, directing
radiation away from the heart and lung, and using functional lung imaging to
identify and avoid areas that are especially perfused.

The study was published in the International Journal of Radiation Oncology,
Biology, Physics.